Prorenin anno 2008

For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease

Selective angiotensin-converting enzyme c-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction

Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations less than or equal to 0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 mumol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximate to 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42 +/- 3 minutes. Quinaprilat increased the t(1/2) approximate to 4-fold, indicating that 71 +/- 6% of Ang I metabolism was attributable to ACE. RXPA380 ( 10 mumol/L) and RXP407 ( 0.1 mmol/L) increased the t(1/2) approximate to 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE ( and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I - induced vasoconstriction in vivo but also why ACEi exert blood pressure - independent effects at low (C-domain - blocking) doses

Bcrp1;Mdr1a/b;Mrp2 combination knockout mice : altered disposition of the dietary carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and its genotoxic metabolites

The multidrug transporters BCRP, MDR1, MRP2 and MRP3 eliminate toxic compounds from tissues and the body, and affect the pharmacokinetics of many drugs and other potentially toxic compounds. The food-derived carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is transported by BCRP, MDR1 and MRP2. To investigate the overlapping functions of Bcrp1, Mdr1a/b and Mrp2 in vivo, we generated Bcrp1;Mdr1a/b;Mrp2-/- mice, which are viable and fertile. These mice, together with Bcrp1;Mrp2;Mrp3-/- mice, were used to study the effects of the multidrug transporters on the pharmacokinetics of PhIP and its metabolites. 30 minutes after oral or i.v. administration of PhIP (1 mg/kg), PhIP levels in small intestine were 4-6-fold reduced in Bcrp1;Mdr1a/b;Mrp2-/- and Bcrp1;Mrp2;Mrp3-/- mice compared to wild-type mice. Fecal excretion of PhIP was 8-20-fold reduced in knockouts. Biliary PhIP excretion was 41-fold reduced in Bcrp1;Mdr1a/b;Mrp2-/- mice. Biliary and small intestinal levels of PhIP metabolites were reduced in Bcrp1;Mrp2-deficient mice. Furthermore, in both knockout strains kidney levels and urinary excretion of genotoxic PhIP-metabolites were significantly increased, suggesting that reduced biliary excretion of PhIP and PhIP-metabolites leads to increased urinary excretion of these metabolites, and increased systemic exposure. Bcrp1 and Mdr1a limited PhIP brain accumulation. In Bcrp1;Mrp2;Mrp3-/-, but not Bcrp1;Mdr1a/b;Mrp2-/- mice, the carcinogenic metabolites N2-OH-PhIP and PhIP-5-sulphate (a genotoxicity marker) accumulated in liver, indicating that Mrp3 is involved in the sinusoidal secretion of these compounds. We conclude that Bcrp1, Mdr1a/b, Mrp2 and Mrp3 significantly affect tissue disposition and biliary and fecal elimination of PhIP and its carcinogenic metabolites and may affect PhIP-induced carcinogenesis as a result